tbuckley/cabot-search huggingface dataset:
Functional characterization of a cycloartenol synthase and four glycosyltransferases in the biosynthesis of cycloastragenol-type astragalosides from Astragalus membranaceus
Authors: Yangyang Duan, Wenyu Du, Zhijun Song, Ridao Chen, Kebo Xie, Jimei Liu, Dawei Chen, Jungui Dai
Journal: Acta Pharmaceutica Sinica B (2022)

Astragalosides are the main active constituents of traditional Chinese medicine Huang-Qi, of which cycloastragenol-type glycosides are the most typical and major bioactive compounds. This kind of compounds exhibit various biological functions including cardiovascular protective, neuroprotective, etc. Owing to the limitations of natural sources and the difficulties encountered in chemical synthesis, re-engineering of biosynthetic machinery will offer an alternative and promising approach to producing astragalosides. However, the biosynthetic pathway for astragalosides remains elusive due to their complex structures and numerous reaction types and steps. Herein, guided by transcriptome and phylogenetic analyses, a cycloartenol synthase and four glycosyltransferases catalyzing the committed steps in the biosynthesis of such bioactive astragalosides were functionally characterized from Astragalus membranaceus. AmCAS1, the first reported cycloartenol synthase from Astragalus genus, is capable of catalyzing the formation of cycloartenol; AmUGT15, AmUGT14, AmUGT13, and AmUGT7 are four glycosyltransferases biochemically characterized to catalyze 3-O-xylosylation, 3-O-glucosylation, 25-O-glucosylation/O-xylosylation and 2ʹ-O-glucosylation of cycloastragenol glycosides, respectively. These findings not only clarified the crucial enzymes for the biosynthesis and the molecular basis for the structural diversity of astragalosides in Astragalus plants, also paved the way for further completely deciphering the biosynthetic pathway and constructing an artificial pathway for their efficient production.
Pre Transcatheter-Aortic Valve Replacement CT Scans: An Opportunity Missed to Detect Lung Cancer?
Authors: Alexis Preston, Bindu Akkanti, Prakash Balan, Biswajit Kar, Igor E. Gregoric, Pushan Jani
Journal: Clinical Cardiology and Cardiovascular Interventions (2022)

Background This study aimed to investigate the incidental pulmonary nodule findings in Trans Catheter Aortic Valve Replacements (TAVR) patients undergoing preoperative computed tomography (CT) scan workup and occurrence of appropriate CT scan follow-up for nodule management in eligible patients. Methods A single-center TAVR data was retrospectively analyzed between 2011 and 2017 to identify the incidental pulmonary nodule finding on preop chest CT scans routinely performed as part of TAVR workup. The primary study objective was to determine incidence of pulmonary nodule and to investigate occurrence of appropriate diagnostic follow-up and cancer in patients eligible for follow-up CT scan based on Fleischner criteria. Results Of the 899 patients (mean age 79 years, 50% male), 220 patients had finding of pulmonary nodule (117 multiple and 103 solitary) and 93 were eligible for a follow-up CT scan based on the Fleischner criteria. Of the 93 follow-up eligible patients, 35 (38%) had repeat CT scan and 58 (62%) had no follow-up CT scan. The lung cancer occurrence in no CT scan, CT within timeframe, CT early and CT delayed groups was 1 each (2% v. 14% v. 7% v. 7%. p=0.3). Conclusion This single center report shows that the pre TAVR CT scans serve as an excellent lung cancer screening opportunity, however most patients (92%) do not have an appropriate follow-up CT scan for the diagnosis and management of the nodules. A larger observational study using the Medicare database may shed more light on real-world practice of pulmonary nodule diagnostic management in TAVR patients.
High-throughput analysis of hematopoietic stem cell engraftment after intravenous and intracerebroventricular dosing
Authors: Robert N. Plasschaert, Mark P. DeAndrade, Fritz Hull, Quoc Nguyen, Tara Peterson, Aimin Yan, Mariana Loperfido, Cristina Baricordi, Luigi Barbarossa, John K. Yoon, Yildirim Dogan, Zeenath Unnisa, Jeffrey W. Schindler, Niek P. van Til, Luca Biasco, Chris Mason
Journal: Molecular Therapy (2022)

Hematopoietic stem/progenitor cell gene therapy (HSPC-GT) has shown clear neurological benefit in rare diseases, which is achieved through the engraftment of genetically modified microglia-like cells (MLCs) in the brain. Still, the engraftment dynamics and the nature of engineered MLCs, as well as their potential use in common neurogenerative diseases, have remained largely unexplored. Here, we comprehensively characterized how different routes of administration affect the biodistribution of genetically engineered MLCs and other HSPC derivatives in mice. We generated a high-resolution single-cell transcriptional map of MLCs and discovered that they could clearly be distinguished from macrophages as well as from resident microglia by the expression of a specific gene signature that is reflective of their HSPC ontogeny and irrespective of their long-term engraftment history. Lastly, using murine models of Parkinson's disease and frontotemporal dementia, we demonstrated that MLCs can deliver therapeutically relevant levels of transgenic protein to the brain, thereby opening avenues for the clinical translation of HSPC-GT to the treatment of major neurological diseases.
Quality of MALDI-TOF mass spectra in routine diagnostics: results from an international external quality assessment including 36 laboratories from 12 countries using 47 challenging bacterial strains
Authors: Aline Cuénod, Martina Aerni, Claudia Bagutti, Banu Bayraktar, Efe Serkan Boz, Cynthia Beisert Carneiro, Carlo Casanova, Alix T. Coste, Peter Damborg, Dirk W. van Dam, Mehmet Demirci, Pavel Drevinek, Olivier Dubuis, José Fernandez, Gilbert Greub, Jaroslav Hrabak, Gülen Hürkal Yiğitler, Jakub Hurych, Thøger Gorm Jensen, Géraldine Jost, Greetje A. Kampinga, Sonja Kittl, Christine Lammens, Claudia Lang, Reto Lienhard, Julie Logan, Carola Maffioli, Ivana Mareković, Matthias Marschal, Jacob Moran-Gilad, Oliver Nolte, Michael Oberle, Michael Pedersen, Valentin Pflüger, Sigrid Pranghofer, Julia Reichl, Rob J. Rentenaar, Arnaud Riat, Belén Rodríguez-Sánchez, Camille Schilt, Ann-Kathrin Schlotterbeck, Jacques Schrenzel, Shani Troib, Elise Willems, Mandy Wootton, Dominik Ziegler, Adrian Egli
Journal: Clinical Microbiology and Infection (2022)

Matrix assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) is a widely used method for bacterial species identification. Incomplete databases and mass spectral quality (MSQ) still represent major challenges. Important proxies for MSQ are the number of detected marker masses, reproducibility, and measurement precision. We aimed to assess MSQs across diagnostic laboratories and the potential of simple workflow adaptations to improve it.For baseline MSQ assessment, 47 diverse bacterial strains, which are challenging to identify by MALDI-TOF MS, were routinely measured in 36 laboratories from 12 countries, and well-defined MSQ features were used. After an intervention consisting of detailed reported feedback and instructions on how to acquire MALDI-TOF mass spectra, measurements were repeated and MSQs were compared.At baseline, we observed heterogeneous MSQ between the devices, considering the median number of marker masses detected (range = [2-25]), reproducibility between technical replicates (range = [55%-86%]), and measurement error (range = [147 parts per million (ppm)-588 ppm]). As a general trend, the spectral quality was improved after the intervention for devices, which yielded low MSQs in the baseline assessment as follows: for four out of five devices with a high measurement error, the measurement precision was improved (p-values <0.001, paired Wilcoxon test); for six out of ten devices, which detected a low number of marker masses, the number of detected marker masses increased (p-values <0.001, paired Wilcoxon test).We have identified simple workflow adaptations, which, to some extent, improve MSQ of poorly performing devices and should be considered by laboratories yielding a low MSQ. Improving MALDI-TOF MSQ in routine diagnostics is essential for increasing the resolution of bacterial identification by MALDI-TOF MS, which is dependent on the reproducible detection of marker masses. The heterogeneity identified in this external quality assessment (EQA) requires further study.
The Heart and Vessels Foreign Bodies. A 3-Year Review
Authors: Emmanuel Auchi Edafe, Maclean Rumokere Akpa
Journal: Clinical Cardiology and Cardiovascular Interventions (2022)

Introduction Foreign bodies in the heart and vessels are rare. They are usually iatrogenic. They get to the heart through different ways. They may cause serous complication including embolism and arrhythmias. They can could be diagnosed with X-ray, computerized tomography, and echocardiography. They are removed by endovascular percutaneous, surgical or conservative. In this four-year review, we analyzed identify and analyzed the treatment of foreign body referred to the Bayelsa Specialist Hospital. Methods We searched the cardiac catherization records of the hospitals and identify 11 foreign bodies referred for the period of 1st January 2018 and 30st April 2021. The site, etiology, clinical presentation, symptoms, complications and management modality, and outcome were noted. Results The patients mean age was 57. There were more women than men 8 versus 4 [P &lt; 0.002]. The most common foreign bodies were parts of inferior vena cava filters and devices. Foreign bodies in the heart were symptomatic in 76% of patients. Right atrial chamber, inferior and superior vena-cava were occupied more often. A total of 78% presented within the first 24 hours. A majority of foreign bodies reached the heart by migration. There was no mortality among those treated with endovascular percutaneous therapy. All those treated in our center were by endovascular percutaneous and conservative therapy. Conclusion Foreign bodies in the heart and vessels may be asymptomatic or present with a wide variety of symptoms. Health care providers should be aware of this rare event and act fast dealing with it.
Standardization of molecular monitoring of CML: results and recommendations from the European treatment and outcome study
Authors: Helen E. White, Matthew Salmon, Francesco Albano, Christina Søs Auður Andersen, Stefan Balabanov, Gueorgui Balatzenko, Gisela Barbany, Jean-Michel Cayuela, Nuno Cerveira, Pascale Cochaux, Dolors Colomer, Daniel Coriu, Joana Diamond, Christian Dietz, Stéphanie Dulucq, Marie Engvall, Georg N. Franke, Egle Gineikiene-Valentine, Michal Gniot, María Teresa Gómez-Casares, Enrico Gottardi, Chloe Hayden, Sandrine Hayette, Andreas Hedblom, Anca Ilea, Barbara Izzo, Antonio Jiménez-Velasco, Tomas Jurcek, Veli Kairisto, Stephen E. Langabeer, Thomas Lion, Nora Meggyesi, Semir Mešanović, Luboslav Mihok, Gerlinde Mitterbauer-Hohendanner, Sylvia Moeckel, Nicole Naumann, Olivier Nibourel, Elisabeth Oppliger Leibundgut, Panayiotis Panayiotidis, Helena Podgornik, Christiane Pott, Inmaculada Rapado, Susan J. Rose, Vivien Schäfer, Tasoula Touloumenidou, Christopher Veigaard, Bianca Venniker-Punt, Claudia Venturi, Paolo Vigneri, Ingvild Vorkinn, Elizabeth Wilkinson, Renata Zadro, Magdalena Zawada, Hana Zizkova, Martin C. Müller, Susanne Saussele, Thomas Ernst, Katerina Machova Polakova, Andreas Hochhaus, Nicholas C. P. Cross
Journal: Leukemia (2022)

Abstract Standardized monitoring of BCR::ABL1 mRNA levels is essential for the management of chronic myeloid leukemia (CML) patients. From 2016 to 2021 the European Treatment and Outcome Study for CML (EUTOS) explored the use of secondary, lyophilized cell-based BCR::ABL1 reference panels traceable to the World Health Organization primary reference material to standardize and validate local laboratory tests. Panels were used to assign and validate conversion factors (CFs) to the International Scale and assess the ability of laboratories to assess deep molecular response (DMR). The study also explored aspects of internal quality control. The percentage of EUTOS reference laboratories ( n = 50) with CFs validated as optimal or satisfactory increased from 67.5% to 97.6% and 36.4% to 91.7% for ABL1 and GUSB , respectively, during the study period and 98% of laboratories were able to detect MR 4.5 in most samples. Laboratories with unvalidated CFs had a higher coefficient of variation for BCR::ABL1 IS and some laboratories had a limit of blank greater than zero which could affect the accurate reporting of DMR. Our study indicates that secondary reference panels can be used effectively to obtain and validate CFs in a manner equivalent to sample exchange and can also be used to monitor additional aspects of quality assurance.
Myeloid-derived growth factor deficiency exacerbates mitotic catastrophe of podocytes in glomerular disease
Authors: Ping Zhan, Yang Zhang, Weichen Shi, Xiaohan Liu, Zhe Qiao, Ziying Wang, Xiaojie Wang, Jichao Wu, Wei Tang, Yu Sun, Yan Zhang, Junhui Zhen, Jin Shang, Min Liu, Fan Yi
Journal: Kidney International (2022)
Structural mechanism of a dual-functional enzyme DgpA/B/C as both a C-glycoside cleaving enzyme and an O- to C-glycoside isomerase
Authors: Pengfei He, Sha Wang, Sen Li, Siqi Liu, Shuqi Zhou, Jing Wang, Jiayue Tao, Dongdong Wang, Rufeng Wang, Wenfu Ma
Journal: Acta Pharmaceutica Sinica B (2022)

The C-glycosidic bond that connects the sugar moiety with aglycone is difficult to be broken or made due to its inert nature. The knowledge of C-glycoside breakdown and synthesis is very limited. Recently, the enzyme DgpA/B/C cascade from a human intestinal bacterium PUE was identified to specifically cleave the C-glycosidic bond of puerarin (daidzein-8-C-glucoside). Here we investigated how puerarin is recognized and oxidized by DgpA based on crystal structures of DgpA with or without substrate and biochemical characterization. More strikingly, we found that apart from being a C-glycoside cleaving enzyme, DgpA/B/C is capable of efficiently converting O- to C-glycoside showing the activity as a structure isomerase. A possible mechanistic model was proposed dependently of the simulated complex structure of DgpB/C with 3″-oxo-daidzin and structure-based mutagenesis. Our findings not only shed light on understanding the enzyme-mediated C-glycosidic bond breakage and formation, but also may help to facilitate stereospecific C-glycoside synthesis in pharmaceutical industry.
Immunoglobulin gene sequence analysis in chronic lymphocytic leukemia: the 2022 update of the recommendations by ERIC, the European Research Initiative on CLL
Authors: Andreas Agathangelidis, Anastasia Chatzidimitriou, Thomas Chatzikonstantinou, Cristina Tresoldi, Zadie Davis, Véronique Giudicelli, Sofia Kossida, Chrysoula Belessi, Richard Rosenquist, Paolo Ghia, Anton W. Langerak, Frédéric Davi, Kostas Stamatopoulos
Journal: Leukemia (2022)

Abstract The somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is a critical biomarker for assessing the prognosis of patients with chronic lymphocytic leukemia (CLL). Importantly, independent studies have documented that IGHV SHM status is also a predictor of responses to therapy, including both chemoimmunotherapy (CIT) and novel, targeted agents. Moreover, immunogenetic analysis in CLL has revealed that different patients may express (quasi)identical, stereotyped B cell receptor immunoglobulin (BcR IG) and are classified into subsets based on this common feature. Patients in certain stereotyped subsets display consistent biology, clinical presentation, and outcome that are distinct from other patients, even with concordant IGHV gene SHM status. All of the above highlights the relevance of immunogenetic analysis in CLL, which is considered a cornerstone for accurate risk stratification and clinical decision making. Recommendations for robust immunogenetic analysis exist thanks to dedicated efforts by ERIC, the European Research Initiative on CLL, covering all test phases, from the pre-analytical and analytical to the post-analytical, pertaining to the analysis, interpretation, and reporting of the findings. That said, these recommendations apply to Sanger sequencing, which is increasingly being superseded by next generation sequencing (NGS), further underscoring the need for an update. Here, we present an overview of the clinical utility of immunogenetics in CLL and update our analytical recommendations with the aim to assist in the refined management of patients with CLL.
Immunocompromised patients have been neglected in COVID-19 trials: a call for action
Authors: Marius Trøseid, Maxime Hentzien, Florence Ader, Sandra Wagner Cardoso, Jose R. Arribas, Jean-Michel Molina, Nicolas Mueller, Maya Hites, Fabrice Bonnet, Oriol Manuel, Dominique Costagliola, Beatriz Grinsztejn, Inge Christoffer Olsen, Yazdan Yazdapanah, Alexandra Calmy
Journal: Clinical Microbiology and Infection (2022)
Fibroblasts Drive Metabolic Reprogramming in Pacemaker Cardiomyocytes
Authors: Pei-Chun Chou, Chih-Min Liu, Ching-Hui Weng, Kai-Chien Yang, Mei-Ling Cheng, Yuh-Charn Lin, Ruey-Bing Yang, Bai-Chuang Shyu, Song-Kun Shyue, Jin-Dian Liu, Shih-Pin Chen, Michael Hsiao, Yu-Feng Hu
Journal: Circulation Research (2022)

The sino atrial node (SAN) is characterized by the microenvironment of pacemaker cardiomyocytes (PCs) encased with fibroblasts. An altered microenvironment leads to rhythm failure. Operable cell or tissue models are either generally lacking or difficult to handle. The biological process behind the milieu of SANs to evoke pacemaker rhythm is unknown. We explored how fibroblasts interact with PCs and regulate metabolic reprogramming and rhythmic activity in the SAN.Tbx18 (T-box transcription factor 18)-induced PCs and fibroblasts were used for cocultures and engineered tissues, which were used as the in vitro models to explore how fibroblasts regulate the functional integrity of SANs. RNA-sequencing, metabolomics, and cellular and molecular techniques were applied to characterize the molecular signals underlying metabolic reprogramming and identify its critical regulators. These pathways were further validated in vivo in rodents and induced human pluripotent stem cell-derived cardiomyocytes.We observed that rhythmicity in Tbx18-induced PCs was regulated by aerobic glycolysis. Fibroblasts critically activated metabolic reprogramming and aerobic glycolysis within PCs, and, therefore, regulated pacemaker activity in PCs. The metabolic reprogramming was attributed to the exclusive induction of Aldoc (aldolase c) within PCs after fibroblast-PC integration. Fibroblasts activated the integrin-dependent mitogen-activated protein kinase-E2F1 signal through cell-cell contact and turned on Aldoc expression in PCs. Interruption of fibroblast-PC interaction or Aldoc knockdown nullified electrical activity. Engineered Tbx18-PC tissue sheets were generated to recapitulate the microenvironment within SANs. Aldoc-driven rhythmic machinery could be replicated within tissue sheets. Similar machinery was faithfully validated in de novo PCs of adult mice and rats, and in human PCs derived from induced pluripotent stem cells.Fibroblasts drive Aldoc-mediated metabolic reprogramming and rhythmic regulation in SANs. This work details the cellular machinery behind the complex milieu of vertebrate SANs and opens a new direction for future therapy.
Endoscopic Surveillance for Premalignant Esophageal Lesions: A Community-Based Multicenter, Prospective Cohort Study
Authors: He Li, Shaokai Zhang, Jinyi Zhou, Feng Tong, Jiyong Gong, Zhenqiu Zha, Ni Li, Changfa Xia, Jiang Li, Liyang Zheng, Pengfei Luo, Renqing Han, Hengmin Ma, Yili Lv, Hongmei Zeng, Rongshou Zheng, Maomao Cao, Fan Yang, Xinxin Yan, Dianqin Sun, Siyi He, Shaoli Zhang, Wanqing Chen, Jie He
Journal: Clinical Gastroenterology and Hepatology (2022)
Aberrant methylmalonylation underlies methylmalonic acidemia and is attenuated by an engineered sirtuin
Authors: PamelaSara E. Head, Sangho Myung, Yong Chen, Jessica L. Schneller, Cindy Wang, Nicholas Duncan, Pauline Hoffman, David Chang, Abigael Gebremariam, Marjan Gucek, Irini Manoli, Charles P. Venditti
Journal: Science Translational Medicine (2022)

Organic acidemias such as methylmalonic acidemia (MMA) are a group of inborn errors of metabolism that typically arise from defects in the catabolism of amino and fatty acids. Accretion of acyl-CoA species is postulated to underlie disease pathophysiology, but the mechanism(s) remain unknown. Here, we surveyed hepatic explants from patients with MMA and unaffected donors, in parallel with samples from various mouse models of methylmalonyl-CoA mutase deficiency. We found a widespread posttranslational modification, methylmalonylation, that inhibited enzymes in the urea cycle and glycine cleavage pathway in MMA. Biochemical studies and mouse genetics established that sirtuin 5 (SIRT5) controlled the metabolism of MMA-related posttranslational modifications. SIRT5 was engineered to resist acylation-driven inhibition via lysine to arginine mutagenesis. The modified SIRT5 was used to create an adeno-associated viral 8 (AAV8) vector and systemically delivered to mutant and control mice. Gene therapy ameliorated hyperammonemia and reduced global methylmalonylation in the MMA mice.
Unaccounted Confounders Limit the Ability to Draw Conclusions From Big Data Analysis Comparing Radiotherapy Fractionation Regimens in NSCLC
Authors: Ahmed Salem, Kevin Franks, Alastair Greystoke, Gerard G. Hanna, Stephen Harrow, Matthew Hatton, Crispin Hiley, Fiona McDonald, Corinne Faivre-Finn
Journal: Journal of Thoracic Oncology (2022)
Time With Diabetes Distress and Glycemia-Specific Distress: New Patient-Reported Outcome Measures for the Psychosocial Burden of Diabetes Using Ecological Momentary Assessment in an Observational Study
Authors: Dominic Ehrmann, Andreas Schmitt, Lilli Priesterroth, Bernhard Kulzer, Thomas Haak, Norbert Hermanns
Journal: Diabetes Care (2022)

OBJECTIVE To estimate time with diabetes distress using ecological momentary assessment (EMA) in people with type 1 diabetes and analyze its associations with glycemic management based on continuous glucose monitoring (CGM). RESEARCH DESIGN AND METHODS We used EMA to assess diabetes distress in a sample of recently hospitalized adults with type 1 diabetes once a day for 17 consecutive days in an ambulatory setting. Additionally, participants were asked daily about hypoglycemia distress (&amp;lt;70 mg/dL [3.9 mmol/L]), hyperglycemia distress (&amp;gt;180 mg/dL [10 mmol/L]), and variability distress (glucose fluctuations). Per person, the percentage of days with elevated distress was calculated (time with distress). Multilevel regression was used to analyze daily associations of distress ratings with CGM-derived parameters. EMA-derived associations between diabetes distress and glycemic outcomes were compared with questionnaire-derived associations. RESULTS Data of 178 participants were analyzed. Participants spent a mean (SD) of days in a state of diabetes distress, 54.6 ± 26.0% in hyperglycemia distress, 45.2 ± 27.5% in variability distress, and 23.0 ± 19.3% in hypoglycemia distress. In multilevel analyses, higher daily ratings of diabetes distress were significantly associated with hyperglycemia (β = 0.41). Results showed high between-person variability as explanation of variance of the models ranged between 22.2 and 98.8%. EMA-derived diabetes distress showed a significant association with mean glucose (r = 0.25), while questionnaire-based diabetes distress did not (r = 0.10). Prospectively, time with diabetes distress was associated with HbA1c at the 3-month follow-up (r = 0.27), while questionnaire-based distress showed no association (r = 0.11). CONCLUSIONS Time with distress as assessed with EMA showed a comparative advantage over distress as determined by questionnaire-based assessment of diabetes distress regarding associations with glycemic management.